The Role of Fbxw7 in genetic instability and cancer

Fbxw7 在遗传不稳定性和癌症中的作用

基本信息

批准号：
7917484
负责人：
Jian-Hua Mao
金额：
$ 35.6万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917484
关键词：
Accounting Address Affect Aneuploidy Apoptosis Blood Brain Breast Breast Cancer Cell Cancer cell line Cells Chromosome Segregation Clinical Code Colon Common Neoplasm Complex DNA Damage Deletion Mutation Development Endometrium Epithelial FBXW7 gene Gene Dosage Genes Genetic Genetic Polymorphism Genomic Instability Goals Growth Human In Vitro Knock-out Knockout Mice Lead Location Lung Lymphocyte Lymphoma Malignant Neoplasms Maps Mediator of activation protein Metabolism Mitosis Mus Mutate Mutation Ovary PTEN gene Pancreas Pathway interactions Predisposition Preventive Prostate Proteins Radiation Research Personnel Resistance Risk Role Signal Transduction Sirolimus Skin Solid Neoplasm Stomach TP53 gene Testing Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitination abstracting aurora-A kinase bile duct bone cancer cell cancer therapy cell growth genetic analysis genetic variant human FRAP1 protein human STK6 protein human disease human tissue in vivo mTOR Inhibitor malignant breast neoplasm mouse model mutant novel programs response tumor

项目摘要

DESCRIPTION (provided by applicant): The role of Fbxw7 in genetic instability and cancer development ABSTRACT Genetic instability is one of the hallmarks of human cancers, particularly in the most common tumors of epithelial origin. The p53 gene is a tumor suppressor with an essential role in induction of growth arrest and apoptosis in response to DNA damage, and is involved in protection from genomic instability. The Fbxw7 gene is a direct transcriptional target of p53 that undergoes deletions and mutations in mouse lymphomas in a p53-dependent manner. Loss of the human FBXW7 gene also leads to genetic instability, and mutations have been detected in cancers from a wide spectrum of human tissues, such as bile duct, blood, bone, brain, breast, colon, endometrium, stomach, lung, ovary, pancreas, and prostate. Alteration of the Fbxw7 gene results in impaired degradation of multiple targets and their consequent accumulation, which may cooperatively contribute to tumor development. However it still remains largely unclear which target is most related to cancer development in Fbxw7-mutant cancer cells. The goal of the first aim is to investigate Fbxw7- mTOR pathway in cancer development. Our preliminary results have shown that mTOR is a new target of Fbxw7, and preliminary genetic analysis of gene copy number changes in human breast cancers gave rise to the intriguing possibility that deletions of FBXW7 and PTEN may be mutually exclusive. We will investigate whether mTOR is required for tumor development in Fbxw7-depelition cells and whether tumors harboring the alteration of Fbxw7 or Pten are sensitive to mTOR inhibitor, such as Rapamycin, treatment. In aim 2, we will elucidate the role of Fbxw7-Aurora-A in genomic instability and tumor development. We will investigate the functional relationship between Fbxw7 and Aurora-A kinase in control of chromosome segregation and aneuploidy, both in vitro and in vivo. In aim 3, we have demonstrated that a functional strain-dependent polymorphism in the N-terminus of Fbxw7 affects the activity of the protein, and influences susceptibility to lymphoma development. We will elucidate the mechanism of action of this genetic variant and determine its role in tumor susceptibility. Therefore we anticipate this project will address critically important questions related to the role of Fbxw7 in tumor development and tumor susceptibility, and possible clinical implications in the therapy of human cancer harboring alteration of FBXW7. PUBLIC RELEVANCE: FBXW7 is emerging as a major human tumor suppressor gene that has been mutated in cancers from a wide spectrum of human tissues, such as bile duct, blood, bone, brain, breast, colon, endometrium, stomach, lung, ovary, pancreas, and prostate. The understanding of the role of FBXW7 in tumor development and tumor susceptibility may provide novel preventive or therapeutic possibilities for many human cancers. 1

描述（由申请人提供）：FBXW7在遗传不稳定性和癌症发展中的作用抽象遗传不稳定性是人类癌症的标志之一，尤其是在上皮起源的最常见肿瘤中。 p53基因是肿瘤抑制因子，在响应DNA损伤的诱导生长停滞和凋亡中起着至关重要的作用，并且参与了免受基因组不稳定性的保护。 FBXW7基因是p53的直接转录靶标，它以p53依赖性方式在小鼠淋巴瘤中经历缺失和突变。人类FBXW7基因的丧失也导致遗传稳定性，并且在各种人体组织（例如胆管，血液，骨，脑，脑，脑，乳腺癌，结肠，子宫内膜，胃，肺，肺，卵巢，卵巢，胰腺，胰腺和前列腺）中发现了突变。 FBXW7基因的改变会导致多个靶标降解及其随之而来的积累，这可能会有助于肿瘤的发展。但是，仍然不清楚哪种靶标与FBXW7突变癌细胞的癌症发展最相关。第一个目的的目的是研究癌症发展中的FBXW7- MTOR途径。我们的初步结果表明，MTOR是FBXW7的新靶标，对人乳腺癌中基因拷贝数变化的初步遗传分析引起了FBXW7和PTEN缺失的有趣可能性。我们将调查FBXW7-脱离细胞中肿瘤发展是否需要MTOR，以及携带FBXW7或PTEN改变的肿瘤是否对MTOR抑制剂（如雷帕霉素）治疗敏感。在AIM 2中，我们将阐明FBXW7-Aurora-A在基因组不稳定性和肿瘤发育中的作用。我们将在体外和体内研究FBXW7和Aurora-A激酶之间的功能关系，以控制染色体分离和非整倍性。在AIM 3中，我们证明了FBXW7 N末端的功能应变依赖性多态性会影响蛋白质的活性，并影响对淋巴瘤发育的易感性。我们将阐明这种遗传变异的作用机理，并确定其在肿瘤易感性中的作用。因此，我们预计该项目将解决与FBXW7在肿瘤发育和肿瘤易感性中的作用有关的至关重要的问题，以及在携带FBXW7改变的人类癌症治疗中的临床意义。公众相关性：FBXW7正在成为一种主要的人类肿瘤抑制基因，该基因已在癌症中被突变的广泛人类组织，例如胆管，血液，血液，骨骼，脑，脑，脑，乳腺癌，结肠，子宫内膜，胃，肺，肺，卵巢，卵巢，胰腺，胰腺和前列腺。对FBXW7在肿瘤发育和肿瘤敏感性中的作用的理解可能为许多人类癌症提供新颖的预防或治疗可能性。 1